Multiple Sclerosis (MS) is an autoimmune disorder mediated by peripheral T lymphocytes that infiltrate and attack the central nervous system (CNS). Understanding important protein regulators that mediate crosstalk between the CNS and immune system during MS and CNS autoimmunity is critical towards developing therapeutic agents. The goal of this proposal is to investigate how amyloid precursor protein (APP) and its metabolic derivative, amyloid-[unreadable]-42 (A[unreadable]42), regulate CNS autoimmunity and general immune cell function. Our laboratory has recently identified an epitope of A[unreadable]42 as a target of adaptive immune responses in the cerebrospinal fluid of relapsing remitting MS (RRMS) patients. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, I have found that in vivo administration of A[unreadable]42 attenuates ascending paralysis, reduces inflammatory lesions in the brain and spinal cord, and suppresses peripheral immune cell activation. Furthermore, in a mouse model lacking APP expression, EAE induction resulted in drastic mortality and behavioral symptoms uncharacteristic of classic EAE disease progression. No CNS inflammation was observed by histological characterization, indicating that the cause of death occurred outside of the CNS. This proposal seeks to extend these initial findings by investigating both the functional necessity of APP in innate and adaptive components of inflammation and the mechanisms by which A[unreadable]42 suppresses immune cell function. Towards these goals, I will use in vivo and in vitro studies including molecular and cellular immunological assays, exploration of the effects of A[unreadable]42 and APP on active and passive EAE induction, and histological characterization of CNS tissue after modulation with A[unreadable]42 and APP. These studies will illuminate a novel and paradoxical role for A[unreadable]42 and APP as beneficial peptides that attenuate peripheral immunity against the CNS. ) PUBLIC HEALTH RELEVANCE: Multiple Sclerosis (MS) is a devastating inflammatory disorder of the central nervous system that affects 1 out of every 700 people annually in the US. The research described here focuses on amyloid-2 and its precursor protein, APP, as critical modulators of autoimmunity that can attenuate inflammation in diseases like MS. The proposed research will provide insights on pathological mechanisms of MS and explore potential therapeutics that could improve the quality of life for those who suffer from the disease.